tbuckley/cabot-search huggingface dataset:
CRISPR base editing of cis-regulatory elements enables the perturbation of neurodegeneration-linked genes
Authors: Colin K.W. Lim, Tristan X. McCallister, Christian Saporito-Magriña, Garrett D. McPheron, Ramya Krishnan, M. Alejandra Zeballos C, Jackson E. Powell, Lindsay V. Clark, Pablo Perez-Pinera, Thomas Gaj
Journal: Molecular Therapy (2022)

CRISPR technology has demonstrated broad utility for controlling target gene expression; however, there remains a need for strategies capable of modulating expression via the precise editing of non-coding regulatory elements. Here, we demonstrate that CRISPR base editors, a class of gene-modifying proteins capable of creating single-base substitutions in DNA, can be used to perturb gene expression via their targeted mutagenesis of cis-acting sequences. Using the promoter region of the human huntingtin (HTT) gene as an initial target, we show that editing of the binding site for the transcription factor NF-κB led to a marked reduction in HTT gene expression in base-edited cell populations. We found that these gene perturbations were persistent and specific, as a transcriptome-wide RNA analysis revealed minimal off-target effects resulting from the action of the base editor protein. We further demonstrate that this base-editing platform could influence gene expression in vivo as its delivery to a mouse model of Huntington's disease led to a potent decrease in HTT mRNA in striatal neurons. Finally, to illustrate the applicability of this concept, we target the amyloid precursor protein, showing that multiplex editing of its promoter region significantly perturbed its expression. These findings demonstrate the potential for base editors to regulate target gene expression.
Combined IFN-γ and JAK inhibition to treat hemophagocytic lymphohistiocytosis in mice
Authors: Josée-Anne Joly, Alexis Vallée, Benoîte Bourdin, Sara Bourbonnais, Natalie Patey, Louis Gaboury, Yves Théorêt, Hélène Decaluwe
Journal: Journal of Allergy and Clinical Immunology (2022)
Postnatal exposure to ambient air pollutants is associated with the composition of the infant gut microbiota at 6-months of age
Authors: Maximilian J. Bailey, Elizabeth A. Holzhausen, Zachariah E. M. Morgan, Noopur Naik, Justin P. Shaffer, Donghai Liang, Howard H. Chang, Jeremy Sarnat, Shan Sun, Paige K. Berger, Kelsey A. Schmidt, Frederick Lurmann, Michael I. Goran, Tanya L. Alderete
Journal: Gut Microbes (2022)

Epidemiological studies in adults have shown that exposure to ambient air pollution (AAP) is associated with the composition of the adult gut microbiome, but these relationships have not been examined in infancy. We aimed to determine if 6-month postnatal AAP exposure was associated with the infant gut microbiota at 6 months of age in a cohort of Latino mother-infant dyads from the Southern California Mother's Milk Study (n = 103). We estimated particulate matter (PM2.5 and PM10) and nitrogen dioxide (NO2) exposure from birth to 6-months based on residential address histories. We characterized the infant gut microbiota using 16S rRNA amplicon sequencing at 6-months of age. At 6-months, the gut microbiota was dominated by the phyla Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Our results show that, after adjusting for important confounders, postnatal AAP exposure was associated with the composition of the gut microbiota. As an example, PM10 exposure was positively associated with Dialister, Dorea, Acinetobacter, and Campylobacter while PM2.5 was positively associated with Actinomyces. Further, exposure to PM10 and PM2.5 was inversely associated with Alistipes and NO2 exposure was positively associated with Actinomyces, Enterococcus, Clostridium, and Eubacterium. Several of these taxa have previously been linked with systemic inflammation, including the genera Dialister and Dorea. This study provides the first evidence of significant associations between exposure to AAP and the composition of the infant gut microbiota, which may have important implications for future infant health and development.
Diabetic Macular Edema and Diode Subthreshold Micropulse Laser
Authors: Noemi Lois, Christina Campbell, Norman Waugh, Augusto Azuara-Blanco, Mandy Maredza, Hema Mistry, Danny McAuley, Nachiketa Acharya, Tariq M. Aslam, Clare Bailey, Victor Chong, Louise Downey, Haralabos Eleftheriadis, Samia Fatum, Sheena George, Faruque Ghanchi, Markus Groppe, Robin Hamilton, Geeta Menon, Ahmed Saad, Sobha Sivaprasad, Marianne Shiew, David H. Steel, James Stephen Talks, Paul Doherty, Cliona McDowell, Mike Clarke
Journal: Ophthalmology (2022)
Molecular determinants of outcomes in relapsed or refractory mantle cell lymphoma treated with ibrutinib or temsirolimus in the MCL3001 (RAY) trial
Authors: Ciara L. Freeman, Prasath Pararajalingam, Ling Jin, Sriram Balasubramanian, Aixiang Jiang, Wendan Xu, Michael Grau, Myroslav Zapukhlyak, Merrill Boyle, Brendan Hodkinson, Michael Schaffer, Christopher Enny, Sanjay Deshpande, Steven Sun, Jessica Vermeulen, Ryan D. Morin, David W. Scott, Georg Lenz
Journal: Leukemia (2022)
Multifunctional graphene oxide nanoparticles for drug delivery in cancer
Authors: Asif Mohd Itoo, Sree Lakshmi Vemula, Mahima Tejasvni Gupta, Mahesh Vilasrao Giram, Sangishetty Akhil Kumar, Balaram Ghosh, Swati Biswas
Journal: Journal of Controlled Release (2022)
Chemically engineering the drug release rate of a PEG-paclitaxel conjugate using click and steric hindrance chemistries for optimal efficacy
Authors: Anne Nguyen, Po-Han Chao, Chun Yat Ong, Elham Rouhollahi, Nojoud AL Fayez, Louis Lin, Jennifer I. Brown, Roland Böttger, Brent Page, Harvey Wong, Shyh-Dar Li
Journal: Biomaterials (2022)
Low‐dose dasatinib 50 mg/day versus standard‐dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: A propensity score analysis
Authors: Elias Jabbour, Koji Sasaki, Fadi G. Haddad, Ghayas C. Issa, Jeffrey Skinner, Sara Dellasala, Musa Yilmaz, Alessandra Ferrajoli, Prithviraj Bose, Philip Thompson, Yesid Alvarado, Nitin Jain, Guillermo Garcia‐Manero, Koichi Takahashi, Gautam Borthakur, Naveen Pemmaraju, Sherry Pierce, Hagop Kantarjian
Journal: American Journal of Hematology (2022)

Low-dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). No randomized trials have compared the outcome with standard-dose dasatinib. This study aims to compare the outcome of patients with CML-CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML-CP treated with low-dose dasatinib (N = 83) or standard-dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4, and MR4.5. Failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) were also compared. Patients on low-dose dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow-up time was 60 months. The 3-year MMR rates were 92% and 84% for low-dose and standard-dose dasatinib, respectively (p = .23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% vs. 66%; p = .04) and MR4.5 (77% vs. 62%; p = .02) at 3 years. The 4-year FFS, EFS and OS rates were 89% versus 77% (p = .04), 95% versus 92% (p = .06), and 97% versus 96% (p = .78) with low-dose and standard-dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure.
Pivotal roles of tumor‐draining lymph nodes in the abscopal effects from combined immunotherapy and radiotherapy
Authors: Zhaoyun Liu, Zhiyong Yu, Dawei Chen, Vivek Verma, Chenxi Yuan, Minglei Wang, Fei Wang, Qing Fan, Xingwu Wang, Yang Li, Yuequn Ma, Meng Wu, Jinming Yu
Journal: Cancer Communications (2022)

Currently, due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects, combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibition (immuno-radiotherapy, iRT) has revolutionized the therapeutic guidelines. It has been demonstrated that tumor-draining lymph nodes (TDLN) are essential for effective antitumor immunity induced by radiotherapy, immunotherapy, or iRT. Given that the function of TDLN in iRT remains unclear, this study aimed to investigate the function and mechanism of TDLN in iRT-induced abscopal effects.The function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN. The flow cytometry, multiple immunofluorescence analysis, and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment. Additionally, we tempted to interrogate the possible mechanisms via RNA-sequencing of tumor-infiltrating lymphocytes and TDLN.TDLN deficiency impaired the control of tumor growth by monotherapy. Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT-stimulated anti-tumor and abscopal effects. Furthermore, in the absence of TDLN, the infiltration of CD45+ and CD8+ T cells was substantially reduced in both primary and abscopal tumors, and the anti-tumor function of CD8+ T cells was attenuated as well. Additionally, the polarization of tumor-associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN. RNA-sequencing data indicated that impaired infiltration and anti-tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment.TDLN play a critical role in iRT by promoting the infiltration of CD8+ T cells and maintaining the M1/M2 macrophage ratio.
Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies
Authors: Panat Yanpiset, Chayodom Maneechote, Sirawit Sriwichaiin, Natthaphat Siri-Angkul, Siriporn C. Chattipakorn, Nipon Chattipakorn
Journal: Acta Pharmaceutica Sinica B (2022)

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction (MI) and myocardial ischemia/reperfusion (MI/R) injury. Due to the limited regenerative ability of cardiomyocytes, understanding the mechanisms of cardiomyocyte death is necessary. Pyroptosis, one of the regulated programmed cell death pathways, has recently been shown to play important roles in MI and MI/R injury. Pyroptosis is activated by damage-associated molecular patterns (DAMPs) that are released from damaged myocardial cells and activate the formation of an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), resulting in caspase-1 cleavage which promotes the activation of Gasdermin D (GSDMD). This pathway is known as the canonical pathway. GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11. Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury. Although the effects of MI or MI/R injury on pyroptosis have previously been discussed, knowledge concerning the roles of GSDMD in these settings remains limited. In this review, the evidence from in vitro, in vivo, and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed. Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease.
Nanoparticles in clinical trials of COVID-19: An update
Authors: Abdur Rauf, Tareq Abu-Izneid, Anees Ahmed Khalil, Nabia Hafeez, Ahmed Olatunde, Md. Mominur Rahman, Prabhakar Semwal, Yahya Saleh Al-Awthan, Omar Salem Bahattab, Ishaq N. Khan, Muhammad Arslan Khan, Rohit Sharma
Journal: International Journal of Surgery (2022)
Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models
Authors: Anna Bershteyn, Lise Jamieson, Hae-Young Kim, Ingrida Platais, Masabho P Milali, Edinah Mudimu, Debra ten Brink, Rowan Martin-Hughes, Sherrie L Kelly, Andrew N Phillips, Loveleen Bansi-Matharu, Valentina Cambiano, Paul Revill, Gesine Meyer-Rath, Brooke E Nichols
Journal: The Lancet Global Health (2022)

In this so-called treat-all era, antiretroviral therapy (ART) interruptions contribute to an increasing proportion of HIV infections and deaths. Many strategies to improve retention on ART cost more than standard of care. In this study, we aimed to estimate the upper-bound costs at which such interventions should be adopted.In this combined analysis, we compared the infections averted, disability-adjusted life-years (DALYs) averted, and upper-bound costs of interventions that improve ART retention in three HIV models with diverse structures, assumptions, and baseline settings: EMOD in South Africa, Optima in Malawi, and Synthesis in sub-Saharan African low-income and middle-income countries (LMICs). We modelled estimates over a 40-year time horizon, from a baseline of Jan 1, 2022, when interventions would be implemented, to Jan 1, 2062. We varied increment of ART retention (25%, 50%, 75%, and 100% retention), the extent to which interventions could be targeted towards individuals at risk of interrupting ART, and cost-effectiveness thresholds in each setting.Despite simulating different settings and epidemic trends, all three models produced consistent estimates of health benefit (ie, DALYs averted) and transmission reduction per increment in retention. The range of estimates was 1·35-3·55 DALYs and 0·12-0·20 infections averted over the 40-year time horizon per additional person-year retained on ART. Upper-bound costs varied by setting and intervention effectiveness. Improving retention by 25% among all people receiving ART, regardless of risk of ART interruption, gave an upper-bound cost per person-year of US$2-6 in Optima (Malawi), $43-68 in Synthesis (LMICs in sub-Saharan Africa), and $28-180 in EMOD (South Africa). A maximally targeted and effective retention intervention had an upper-bound cost per person-year of US$93-223 in Optima (Malawi), $871-1389 in Synthesis (LMICs in sub-Saharan Africa), and $1013-6518 in EMOD (South Africa).Upper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART.Bill & Melinda Gates Foundation.
Monkeypox: another test for PCR
Authors: Jim F Huggett, David French, Denise M O’Sullivan, Jacob Moran-Gilad, Alimuddin Zumla
Journal: Eurosurveillance (2022)

Monkeypox was declared a public health emergency of international concern by the World Health Organization (WHO) on 23 July 2022. Between 1 January and 23 July 2022, 16,016 laboratory confirmed cases of monkeypox and five deaths were reported to WHO from 75 countries on all continents. Public health authorities are proactively identifying cases and tracing their contacts to contain its spread. As with COVID-19, PCR is the only method capable of being deployed at sufficient speed to provide timely feedback on any public health interventions. However, at this point, there is little information on how those PCR assays are being standardised between laboratories. A likely reason is that testing is still limited on a global scale and that detection, not quantification, of monkeypox virus DNA is the main clinical requirement. Yet we should not be complacent about PCR performance. As testing requirements increase rapidly and specimens become more diverse, it would be prudent to ensure PCR accuracy from the outset to support harmonisation and ease regulatory conformance. Lessons from COVID-19 should aid implementation with appropriate material, documentary and methodological standards offering dynamic mechanisms to ensure testing that most accurately guides public health decisions.
The Concept of Strength Through Synergy Applied to the Search of Powerful Prognostic Biomarkers in Gastroesophageal Cancer
Authors: Roberto C. Delgado Bolton, Adriana K. Calapaquí Terán, Stefano Fanti, Francesco Giammarile
Journal: Clinical Nuclear Medicine (2022)

Abstract Integrating clinical and pathological data together with imaging-derived information, such as radiomics and sarcopenia status, creating new combined biomarkers that increase the prognostic value compared with each of them used independently. The concept of strength through synergy, applicable in so many areas of life, is also demonstrated in this area of science and opens up innumerable pathways for improving patient care in cancer. This is as an example on how we can explore and make the most of all the information we already have (clinical, pathological, imaging), without the need for new invasive tests.
Kidney outcomes in patients with diabetes mellitus did not differ between individual sodium-glucose cotransporter-2 inhibitors
Authors: Yuta Suzuki, Hidehiro Kaneko, Akira Okada, Satoshi Matsuoka, Katsuhito Fujiu, Nobuaki Michihata, Taisuke Jo, Norifumi Takeda, Hiroyuki Morita, Koichi Node, Masaomi Nangaku, Hideo Yasunaga, Issei Komuro
Journal: Kidney International (2022)
Enhanced bedside mortality prediction combining point-of-care lactate and the quick Sequential Organ Failure Assessment (qSOFA) score in patients hospitalised with suspected infection in southeast Asia: a cohort study
Authors: Shelton W Wright, Viriya Hantrakun, Kristina E Rudd, Chuen-Yen Lau, Khie Chen Lie, Nguyen Van Vinh Chau, Prapit Teparrukkul, T Eoin West, Direk Limmathurotsakul
Journal: The Lancet Global Health (2022)

Simple, bedside prediction of infection-related mortality in low-resource settings is crucial for triage and resource-utilisation decisions. We aimed to evaluate mortality prediction by combining point-of-care venous lactate with the quick Sequential Organ Failure Assessment (qSOFA) score in adult patients admitted to hospital with suspected infection in southeast Asia.We performed a cohort study by prospectively enrolling patients aged 18 years or older who had been admitted to hospital within the previous 24 h for suspected infection (with at least three documented systemic manifestations of infection according to the 2012 Surviving Sepsis Campaign) at Sunpasitthiprasong Hospital in Ubon Ratchathani, Thailand (derivation cohort). Venous lactate concentration was determined by a point-of-care device and multiple scores were developed. We then evaluated candidate 28-day mortality prediction models combining qSOFA and the lactate scores. A final model was compared with the qSOFA score, a lactate score, and a modified Sequential Organ Failure Assessment (SOFA) score for mortality discrimination using the area under the receiver operating characteristic curve (AUROC). Mortality discrimination of the qSOFA-lactate score was then verified in an external, prospectively enrolled, multinational cohort in southeast Asia.Between March 1, 2013, and Jan 26, 2017, 5001 patients were enrolled in the derivation cohort; 4980 had point-of-care lactate data available and were eligible for analysis, and 816 died within 28 days of enrolment. The discrimination for 28-day mortality prediction of a qSOFA-lactate score combining the qSOFA score and a lactate score was superior to that of the qSOFA score alone (AUROC 0·78 [95% CI 0·76-0·80] vs 0·68 [0·67-0·70]; p<0·0001) and similar to a modified SOFA score (0·77 [0·75-0·78]; p=0·088). A lactate score alone had superior discrimination compared with the qSOFA score (AUROC 0·76 [95% CI 0·74-0·78]; p<0·0001). 815 patients were enrolled in the external validation cohort and 792 had point-of-care lactate data and were included in the analysis; the qSOFA-lactate score (AUROC 0·77 [95% CI 0·73-0·82]) showed significantly improved 28-day mortality discrimination compared with the qSOFA score alone (0·69 [0·63-0·74]; p<0·0001).In southeast Asia, rapid, bedside assessments based on point-of-care lactate concentration combined with the qSOFA score can identify patients at risk of sepsis-related mortality with greater accuracy than the qSOFA score alone, and with similar accuracy to a modified SOFA score.National Institutes of Health, Wellcome Trust.
How can assessing hemodynamics help to assess volume status?
Authors: Daniel De Backer, Nadia Aissaoui, Maurizio Cecconi, Michelle S. Chew, André Denault, Ludhmila Hajjar, Glenn Hernandez, Antonio Messina, Sheila Nainan Myatra, Marlies Ostermann, Michael R. Pinsky, Jean-Louis Teboul, Philippe Vignon, Jean-Louis Vincent, Xavier Monnet
Journal: Intensive Care Medicine (2022)
18F-Fluciclovine PET Detected Early Tumor Recurrence in Prostatectomy Bed With Low PSA of 0.3 ng/mL But Negative on 18F-PSMA PET Scan
Authors: Trinh T. Nguyen, Priya R. Bhosale, Yang Lu
Journal: Clinical Nuclear Medicine (2022)

A 58-year-old man with metastatic prostate cancer was treated with prostatectomy, radiation therapy to bone metastasis, and androgen deprivation therapy plus abiraterone. He had posttreatment nadir PSA of 0.1 ng/mL. A follow-up 18 F-fluciclovine PET performed with PSA of 0.3 ng/mL showed a focal tracer-avid lesion in the left prostatectomy bed. This lesion was negative on 18 F-DCFPyL PET/CT, but with typical MRI features for disease recurrence. Minimal urinary activity of fluciclovine helped detection of local disease recurrence in the prostatectomy bed.